The object of this study is to clarify the physiology and pathophysiology of insulin secretion in man, with particular emphasis on the specific ways in which a variety of stimuli lead to the release of insulin. It is proposed to accomplish this objective by measurement of serum insulin and glucose levels during studies in which glucose and secretin are given in such a manner as to stimulate insulin release from one of the several specific functional pools recently described to be present in the islets. Dose response curves are to be prepared in normal human subjects for both of these substances for insulin output from the acute and the slowly responding pools. We plan to analyze quantitatively the specific abnormalities in subjects with carbohydrate intolerance (diabetes mellitus), obesity, and lipemia. In the dog, studies are proposed to determine the importance of the autonomic nervous system in the regulation of insulin secretion. Pancreatic nerves will be isolated and stimulated in such a manner as to determine the effects of sympathetic stimulation and parasympathetic stimulation on pancreatic insulin output from the cannulated pancreaticoduodenal vein, by analysis of insulin levels and extracorporeal blood flow. Recordings from mixed nerves will be made to relate the frequency of neural discharge to induced pathophysiological stimuli to the sympathetic nervous system, such as shock and hypoxia and to the parasympathetic system, such as intrathecally conditioned neurally related insulin release.